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Nucleic Acids Res. 2016 Feb 29;44(4):1703-17. doi: 10.1093/nar/gkv1473. Epub 2015 Dec 17.

The spliceosome-associated protein Nrl1 suppresses homologous recombination-dependent R-loop formation in fission yeast.

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  • 1Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, Vienna A-1030, Austria Department of Oncology, Stanford University, Stanford 94305, USA
  • 2CRUK/MRC Oxford Institute for Radiation Oncology, Oxford OX37DQ , UK.
  • 3Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, Vienna A-1030, Austria.
  • 4Department of Medical Biochemistry, Max F. Perutz Laboratories,Medical University of Vienna, Vienna A-1030, Austria.
  • 5Cancer Research Institute, Slovak Academy of Sciences, Bratislava 81438, Slovakia.
  • 6Max F. Perutz Laboratories, Mass Spectrometry Facility, Vienna A-1030, Austria.
  • 7University of Southern California, Los Angeles 90089-0911, USA.
  • 8CRUK/MRC Oxford Institute for Radiation Oncology, Oxford OX37DQ , UK


The formation of RNA-DNA hybrids, referred to as R-loops, can promote genome instability and cancer development. Yet the mechanisms by which R-loops compromise genome instability are poorly understood. Here, we establish roles for the evolutionarily conserved Nrl1 protein in pre-mRNA splicing regulation, R-loop suppression and in maintaining genome stability. nrl1Δ mutants exhibit endogenous DNA damage, are sensitive to exogenous DNA damage, and have defects in homologous recombination (HR) repair. Concomitantly, nrl1Δ cells display significant changes in gene expression, similar to those induced by DNA damage in wild-type cells. Further, we find that nrl1Δ cells accumulate high levels of R-loops, which co-localize with HR repair factors and require Rad51 and Rad52 for their formation. Together, our findings support a model in which R-loop accumulation and subsequent DNA damage sequesters HR factors, thereby compromising HR repair at endogenously or exogenously induced DNA damage sites, leading to genome instability.

© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

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